Shortly after our laboratory discovered that nitroxides, which have been used as EPR spin labels exhibit superoxide dismutase (SOD) activity, we have shown that they are quite effective agents in protecting cells against oxidative stress. Our lead compound, Tempol, a water soluble nitroxide has been shown to protect mammalian cells against superoxide generated from xanthine/xanthine oxidase, and direct hydrogen peroxide cytotoxicity. More recently we have demonstrated that Tempol protects both cells in vitro and mice against ionizing radiation. Screening of an additional eight water soluble nitroxides has revealed at least two nitroxides that are more efficient than Tempol. Thus, the nitroxides represent a new class of radiation protectors that may have widespread use in protecting humans against radiation. Studies are underway to determine if selected nitroxides might exert differential protection between normal and tumor tissue. Topically applied Tempol has been shown to protect against radiation-induced alopecia in guinea pigs. Tempol has been shown to protect cells against mutation induction mediated by superoxide, hydrogen peroxide, and radiation. Tempol has also been shown to protect cells exposed to various chemotherapy drugs including mitomycin C and SR-4233. Not only might these agents be useful in protecting against certain chemotherapy agents but should be instructive in determining mechanisms of action. Since these agents readily penetrate cell membranes, they may be of use in other areas of medical research such as ischemia/reperfusion injury studies. Published data already confirm their utility in this setting.